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Early Streptococcus pneumoniae serotype changes in Utah adults after the introduction of PCV13 in children
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Early Streptococcus pneumoniae serotype changes in Utah adults after the introduction of PCV13 in children Brian A. Kendall a,∗,1 , Kristin K. Dascomb a,b,1 , Rajesh R. Mehta b , Chris Stockmann d , Edward O. Mason c , Krow Ampofo d , Andrew T. Pavia d , Carrie L. Byington d a
Departments of Medicine and Pathology, University of Utah, Salt Lake City, UT, USA Department of Infectious Diseases, Intermountain Healthcare, Murray, UT, USA c Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA d Department of pediatrics, University of Utah, Salt Lake City, UT, USA b
a r t i c l e
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Article history: Received 2 June 2015 Received in revised form 14 November 2015 Accepted 2 December 2015 Available online xxx Keywords: Streptococcus pneumoniae Invasive pneumococcal disease Pneumococcal vaccines Epidemiology
a b s t r a c t Introduction: Pneumococcal conjugate vaccines (PCV) have indirect effects due to decreased Streptococcus pneumoniae colonization in vaccine recipients. We sought to determine whether the introduction of PCV13 in children led to changes in the epidemiology and clinical manifestations of invasive pneumococcal disease (IPD) in adults. Methods: We described demographics, comorbidities, clinical manifestations, and serotypes of IPD in Utah adults before (November 2009−February 2010) and after (March 2010−March 2012) the introduction of PCV13 in children. We also compare serotypes causing IPD in Utah adults and children. Results: After the introduction of PCV13 in the childhood vaccine program, the proportion of IPD due to PCV13 exclusive serotypes decreased significantly in Utah adults (64−40%, p = 0.009), primarily due to a decline in serotype 7F (36−15%, p = 0.008). There were non-significant increases in IPD due to Pneumococcal polysaccharide 23 (PPV23) unique serotypes and non-vaccine serotypes, most notably serotype 22F. Changes in the proportions of vaccine and non-vaccine serotypes were similar in adults and children. Meningitis was more commonly due to non-vaccine serotypes relative to non-meningitis cases (47% vs. 18%, p = 0.007). When stratified by sex, decreases in PCV13 serotype IPD were only noted in men (76−33%, p = 0.001). Conclusions: Serotype epidemiology of IPD in adults closely follows that of children in the PCV13 era. Continued surveillance is needed to confirm whether replacement serotypes will lead to increases in pneumococcal meningitis and whether there are sex differences in the indirect effects of PCV vaccination in children. © 2015 Published by Elsevier Ltd.
1. Introduction The use of conjugate pneumococcal vaccines has resulted in selection pressure leading to rapid changes in the serotypes responsible for invasive pneumococcal disease (IPD) [1,2]. Conjugate vaccines not only impact the vaccine recipient, but also are thought to decrease pharyngeal carriage of Streptococcus pneumoniae via induction of mucosal antibodies [3] and possibly lead to indirect protection of vaccine non-recipients. The population effects of pneumococcal conjugate vaccines are complex and may lead to
∗ Corresponding author at: Departments of Medicine and Pathology, University of Utah, Salt Lake City, Utah, 30N 1900 E, Room 4B120, Salt Lake City, UT 84132, USA. E-mail address: [email protected] (B.A. Kendall). 1 The first two authors contributed equally to the preparation of this manuscript.
changes in both the epidemiology and the clinical manifestations of IPD. For instance, after the introduction of 7-valent pneumococcal conjugate vaccine (PCV7), changes in IPD complications such as empyema emerged rapidly in Utah children [4] prior to increasing nationally [5,6]. Empyema was most often due to serotypes not covered by PCV7 but included in the newer 13-valent pneumococcal conjugate vaccine (PCV13), including serotypes 1, 3, 7F, and 19A. We sought to determine if the institution of PCV13 in Utah children indirectly led to early changes in the serotypes responsible and the clinical syndromes seen in IPD in Utah adults.
2. Methods This study was approved by the institutional review boards of Intermountain Healthcare (Intermountain) and the University of
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Please cite this article in press as: Kendall BA, et al. Early Streptococcus pneumoniae serotype changes in Utah adults after the introduction of PCV13 in children. Vaccine (2015), http://dx.doi.org/10.1016/j.vaccine.2015.12.010
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Table 1 Demographics, clinical characteristics, and outcome for adults PRE- and POST- approval of 13-valent pneumococcal conjugate vaccine.
Age by percentage <40 40-64 >65 Sex- percent male Race Caucasian Non-Caucasian Unknown PPV23 vaccination documented in EMR Comorbidities Alcohol abuse Diabetes HIV Neurologic disease Cardiovascular disease Pulmonary disease Renal disease Hepatic disease Hematologic malignancy Bone marrow transplant Solid organ malignancy Solid organ transplant Splenectomy Other immunocompromising therapy Clinical syndromes Bacteremia Occult bacteremia Bacteremic pneumonia Pleural effusion Meningitis Sinusitis Otitis media Mastoiditis Outcomes ICU admission Ventilator days (SD) Ever required vasopressors Death associated with hospitalization
PRE-PCV13 November 1, 2009−February 28, 2010 N = 36
POST-PCV13 March 1, 2010–March 31, 2012 N = 152
p-value
16.7 55.6 27.8 58.3
15.8 46.1 38.2 51.3
0.88 0.31 0.25 0.65
77.8 16.65.6 27.8
84.2 11.93.9 30.3
0.37 0.440.66 0.78
0 25.0 0 13.9 27.8 30.6 19.4 5.6 11.1 0 11.1 2.8 2.8 13.9
6.6 25.0 1.3 9.2 31.6 30.3 8.6 6.6 8.6 2.0 9.2 2.6 0.7 9.9
0.21 0.98 0.65 0.41 0.67 1.0 0.07 1.0 0.75 1.0 0.75 1.0 0.35 0.55
97.2 11.1 77.8 17.1 8.3 2.8 2.8 2.8
99.3 9.9 77.0 18.2 9.2 5.3 4.6 2.6
0.35 0.76 1.0 1.0 1.0 1.0 1.0 1.0
33.3 0.7(2.0) 11.1 5.6
32.2 1.7(3.9) 15.1 9.2
1.0 0.14 0.79 0.74
Utah. We systematically collected pneumococcal isolates from sterile site cultures obtained from adults 18 years and older cared for within the Intermountain Healthcare system from November 2009 through March 2012. All isolates were identified at the Intermountain central laboratory, and stored at the LDS Hospital clinical epidemiology laboratory. The central laboratory performs microbial identification for 18 of 20 Intermountain adult inpatient facilities, as well as several outpatient clinics. Intermountain Healthcare has an overall market share of 56% of the adult population in the state of Utah (approximately 2,040,000 adults in 2014). Streptococcus pneumoniae was identified by Gram stain, colony morphology, and optochin sensitivity. Identification was confirmed by the BD Phoenix Automated Microbiology System (BD Diagnostics, Franklin Lakes, NJ, USA). We performed serotyping on all isolates at the Baylor College of Medicine using the capsular swelling method [7]. IPD was defined as isolation of S. pneumoniae from blood, cerebrospinal fluid, ascites, pleural fluid, pericardial fluid, joint fluid, or internal body site. We obtained demographic, clinical, and microbiologic data from the Intermountain Enterprise Data Warehouse (EDW), an electronic storage site for data from patients receiving care at all Intermountain facilities. Two infectious diseases physician researchers (BK, KD) independently abstracted comorbidity data from available electronic physician notes. We considered comorbidities to be chronic diseases requiring ongoing medical care at the time of IPD. In cases where the two reviewers disagreed, classification of chronic diseases was adjudicated by group consensus.
Data regarding pneumococcal polysaccharide vaccination (PPV23) were abstracted from inpatient physician notes and electronic pharmacy records. Outpatient vaccine records were not available. We compared the frequency of clinical isolates included in PCV7, PCV13, PPV23, and non-vaccine serotypes identified before and again after the introduction of PCV13. We defined the ‘PRE’ period as November 1, 2009 through February 28, 2010 and the ‘POST’ period as March 1, 2010 through March 31, 2012. Isolates prior to November, 2009 were not archived, limiting the PRE period duration. PCV13 was licensed for use on February 24, 2010 and was rapidly introduced into the childhood vaccine schedule [8]. We performed additional univariate analyses stratifying by age and gender. We compared adult serotypes with IPD isolates collected from children under 18 treated during the same time periods at Primary Children’s Hospital. A detailed description of the pediatric cohort has been published previously [9]. Using SPSS for windows (IBM, Armonk, NY, USA), we examined associations between clinical and demographic characteristics of patients with individual serotypes and serotypes grouped by inclusion or exclusion from available vaccines. We used the Chi-square test or Fisher exact test for categorical variables and Student’s t-test or Mann-Whitney U-test for continuous variables. 3. Results We identified 200 isolates from 196 adults with cultureconfirmed IPD based on search of the EDW (Table 1). Six isolates
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did not exhibit capsular swelling when exposed to typed anti-sera and therefore serotype would not be determined. In addition, two isolates were from outpatients with no electronic medical records available for review, leaving 188 samples for analysis. There were no significant differences in demographic characteristics or comorbidities between the PRE- and POST-PCV13 groups (Table 1). Comorbidities were similar to those described in other cohorts [10].
Table 2 Changes in the frequency of Adult IPD Streptococcus pneumoniae serotypes before and after introduction of conjugated pneumococcal vaccine in Children in Utah, stratified by gender.
Gender Male PCV7 serotypes PCV13 serotypesa PPV23 serotypesb Nonvax serotypes Gender Female PCV& serotypes PCV13 serotypesa PPV23 serotypesb Nonvax serotypes
3.1. Serotype distribution of IPD isolates There were six isolates of PCV7 serotypes among Utah adults accounting for 3% isolates identified during the study period, 0 in the PRE period and six of 152 (4%) in the POST period. Serotypes exclusive to PCV13 declined, from 23/36 (64%) in the PRE period to 60/152 (40%) in the POST period (p = 0.009). (Figs. 1 and 2) This reduction is primarily due to a decrease in PCV13 serotype 7F, which accounted for 13/36 (36%) of isolates in the PRE period and declined to 23/152 (15%) of all isolates in the POST period (p = 0.008) A non-significant decrease was also seen in PCV13 type 3 but not in type 19A (Fig. 1). Serotypes in PPV23 but not in PCV13 increased from 9/36 (25%) in the PRE period to 55/152 (36%) in the POST period (p = 0.25). (Fig. 2a) PPV23 types 8 and 22F both increased slightly (1/36 [3%] to 14/152 [9%] (p = 0.25), and 2/36 [6%] to 17/152 [11%] (p = 0.39), respectively)(Fig. 1). Serotypes not present in any vaccine increased from 3/36 (8%) to 32/152 (21%) (p = 0.10). No individual serotype dominated in the POST period.
3.2. Comparison of adult and child serotype distributions There were 87 isolates collected from children (median age 2.9 {range: 0−15.8 years; 62% male): 12 in the PRE period and 75 from the POST period. The same trends were identified with nonsignificant decreases in the six additional serotypes contained in PCV13 (6/12 [50%] to 32/75 [43%] p = 0.79. PPV23 unique types and non-vaccine types increased (1/12 [1%] to 17/75 [23%] p = 0.46) and 1/12 [1%] to 23/75 [31%] p = 0.29, respectively). Changes in adult serotypes mirrored those in children (Fig. 2a for adults and Fig. 2b for children).
3.3. Serotypes and clinical presentation We observed no significant changes in clinical syndromes after the introduction of PCV13 (Table 1). Bacteremic pneumonia was the most common syndrome in both eras. There was no increase in the proportion of patients presenting with pleural disease. Across both eras, nearly half of the meningitis isolates were non-PCV13 types (8 of 17 [47%]). Non-PCV13 serotypes made up a significantly larger proportion of isolates from meningitis cases relative to nonmeningitis cases (8/17 [47%] vs. 30/171 [18%], [p = 0.007].
3.4. Serotype changes by sex When we stratified the data by sex, we found significant differences in the vaccine serotypes accounting for IPD in men and women (Table 2), though there was no difference in PPV23 vaccination rates between men and women (p = 0.78). Men had more disease due to the six additional PCV13 serotypes in the PRE-PCV13 era (PCV13 16/21 [76%] vs. 7/15 [47%] in women). In the POST PCV13 period, men had a significant decline in PCV13 serotypes isolated (decline to 26/78 [33%] [p = 0.001]) with no change demonstrated in women (7/15 [47%] in the PRE to 34/74 [46%] in the POST, p = 0.73).
3
a b
PRE-PCV13 N = 36
POST-PCV13 N = 152
0% (n = 0) 76.2% (n = 16) 19.0% (n = 4) 4.8% (n = 1)
5.1% (n = 4) 33.3% (n = 26) 34.6% (n = 27) 26.9% (n = 21)
p = 0.42 p = 0.001 p = 0.23 p = 0.03
0 (n = 0) 46.7% (n = 7) 26.7% (n = 4) 26.7% (n = 4)
2.7% (n = 2) 45.9% (n = 34) 24.3% (n = 18) 27.0% (n = 20)
p = 0.68 p = 0.73 p = 0.68 p = 0.83
Six additional serotypes not present in PCV7. Serotypes unique to PPV23.
4. Discussion Our data demonstrate that the introduction of pneumococcal conjugate vaccines in the childhood immunization schedule has been associated with significant changes in the serotype distribution in Utah adults. PCV7 serotypes were rare and PCV13 unique serotypes significantly declined in both adults and children very soon after childhood vaccine introduction. Non-PCV-13 serotypes observed in adults mirrored those seen in the pediatric population and included serotypes found in the PPV23 (8 and 22F) and those that are not found in any licensed vaccine (16, and 35). We observed that meningitis cases were more often due to non-vaccine serotypes relative to non-meningitis cases. We identified a sexspecific effect on the distribution of serotypes causing IPD Introduction of PCV-7 into the pediatric vaccine schedule in 2000 lead to rapid and substantial declines in vaccine-type IPD[11] in all age groups, with the most dramatic decreases in young children targeted for immunization. PCV coverage in Utah has been excellent with greater than 80% of children 19−35 months of age receiving four PCV shots by by the end of 2011, providing strong potential for indirect immunity [12]. We previously reported a decrease in the frequency of vaccine-type IPD among Utah adults [13]. The continued absence of PCV7 serotypes and the decline in PCV13 serotypes in adults immediately after the introduction of PCV13 in children argues further that conjugate pneumococcal vaccines in children have a significant impact on the epidemiology of IPD in adults. Conjugate vaccines lead to decreased colonization in children due to the near elimination of vaccine-type pneumococci, likely leading to indirect protection of adults [14]. Our data suggest that indirect protection may emerge rapidly in adults after new conjugated vaccines are introduced in the childhood population. Prior to the introduction of PCV-13, serotype 7F was the most common cause of IPD among Utah adults and children [9,13,15]. This study demonstrated that following introduction of PCV13 serotype 7F declined rapidly and significantly in adults. The decline of type 7F in children was also significant when a longer-PRE period, unavailable for adult analysis, was evaluated (unpublished data). PCV13 serotype 3 declined, but not significantly, and 19A did not decline. One possible explanation is decreased type-specific vaccine immunogenicity [16,17] There is evidence that PCV13 does not lead to a robust immune response against serotype 3; in one study, only 64% of children mounted an adequate antibody response compared with 90−98% with the other new serotypes [18]. The reason that type 19A did not decline is unclear though another group reported persistent carriage rates of 19A in the POST PCV13 era [19]. The relatively high frequency of types 8 and 22F, serotypes of known pathogenicity [20], corresponds with increasing prevalence noted in other studies [21,22]. Both serotypes are components of
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Fig. 1. Changes in IPD serogroup/type frequency by proportion of the total isolates for the periods PRE and POST introduction of 13 valent conjugated pneumococcal vaccine in children, February 2010 (n = 188).
Fig. 2. Changes in the proportion of vaccine type IPD in (a) adults and (b) children PRE and POST introduction of PCV13. PPV23 serotypes are those unique to this vaccine. PCV13 serotypes are the six additional types not present in PCV7.
PPV23 but inclusion of these types in future conjugate vaccines may also be beneficial. The large proportion of non-vaccine serotypes among meningitis cases may be reason for concern. Non-vaccine serotypes 35B, 35F, 15C, and 6C were present in our meningitis cohort and have been associated with meningitis in Utah children, as well as adults and children from national surveillance data. [23,24]. Continued national and regional surveillance will be critical to determining whether serotype replacement will result in increasing meningitis frequency as was determined with empyema [5,6,25]. The differential representation of serotypes by sex has not been previously reported. This result may be explained by differences in
the immunogenicity of polysaccharide vaccines. Many viruses and bacteria have been shown to induce different antibody responses in men and women [26,27] and anthrax vaccines cause more localized inflammation in women than in men [26]. Recently, Wiemken et al. [28] found that PPV23 protected women older than 65 from hospitalization due to pneumococcal pneumonia but did not protect men. In our cohort, men had more PRE-PCV13 disease due to vaccine types included in both PCV13 and PPV23 (of which there is considerable overlap), a finding that could be explained by less effective PPV23 vaccine response. The increase (though nonsignificant) in disease due to PPV23 unique serotypes in men and stability of such disease in women also supports this hypothesis.
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While the numbers in our study are small, if this finding is confirmed in larger cohorts, men may realize more indirect benefit of pediatric conjugate vaccines. Our study has several limitations. Our cohort is not truly population-based, however Intermountain Healthcare provides 56% of the medical care for adults and 85% of care for children in Utah and we believe that our results are likely representative of IPD in our region. We only collected isolates from sterile sources; therefore, our data are only representative of serotypes involved in invasive disease and may not be representative of serotypes causing localized disease (e.g. sinusitis, otitis media, pneumonia without bacteremia). In spite of these limitations, our data provide evidence that conjugate vaccines in children produce indirect protective effects in adult IPD remarkably soon after their introduction into the community. Serotype replacement also appears to occur quickly and may have clinically significant consequences [2,29]. A difference in vaccine response between genders deserves close scrutiny as a possible factor in vaccine effectiveness. Funding This work was supported by Intermountain Healthcare and the University of Utah. Acknowledgments The authors would like to thank George Hinde and Esar Chickrie for laboratory assistance. Conflict of interest statement BAK is supported by an investigator-initiated grant from Merck and Co., Inc. to study methods for the diagnosis of communityacquired pneumonia due to S. pneumoniae. KKD is supported by an investigator-initiated grant from Pfizer, Inc. to study pneumococcal serotype distribution in Utah adults with pneumonia. CS is supported by the American Foundation for Pharmaceutical Education’s Clinical Pharmaceutical Sciences Fellowship. CLB has intellectual property in and receives royalties from BioFire Diagnostics. CLB is supported by NIH/NCATS 1UL1TR001067 and by the HA and Edna Benning Presidential Endowment. References [1] Moore MR, Link-Gelles R, Schaffner W, Lynfield R, Lexau C, Bennett NM, et al. Effect of use of 13-valent pneumococcal conjugate vaccine in children on invasive pneumococcal disease in children and adults in the USA: analysis of multisite, population-based surveillance. Lancet Infect Dis 2015;15(March (3)):301–9. [2] Stockmann C, Byington CL. PCV13 in the USA: early successes and potential challenges. Lancet Infect Dis 2015;15(March (3)):254–6. [3] Ghaffar F, Barton T, Lozano J, Muniz LS, Hicks P, Gan V, et al. Effect of the 7-valent pneumococcal conjugate vaccine on nasopharyngeal colonization by Streptococcus pneumoniae in the first 2 years of life. Clin Infect Dis 2004;39(October (7)):930–8. [4] Ampofo K, Pavia AT, Stockmann CR, Blaschke AJ, Weng HY, Korgenski KE, et al. Evolution of the epidemiology of pneumococcal disease among Utah children through the vaccine era. Pediatr Infect Dis J 2011;30(December (12)):1100–3. [5] Li ST, Tancredi DJ. Empyema hospitalizations increased in US children despite pneumococcal conjugate vaccine. Pediatrics 2010;125(January (1)):26–33. [6] Grijalva CG, Nuorti JP, Zhu Y, Griffin MR. Increasing incidence of empyema complicating childhood community-acquired pneumonia in the United States. Clin Infect Dis 2010;50(March (6)):805–13.
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Impact of the 13-valent pneumococcal conjugate vaccine on nasopharyngeal carriage of Streptococcus pneumoniae among children attending group daycare in southeastern France. Pediatr Infect Dis J 2015;34(March (3)):286–8. [20] Harboe ZB, Thomsen RW, Riis A, Valentiner-Branth P, Christensen JJ, Lambertsen L, et al. Pneumococcal serotypes and mortality following invasive pneumococcal disease: a population-based cohort study. PLoS Med 2009;6(May (5)):e1000081. [21] Jacobs MR, Good CE, Bajaksouzian S, Windau AR. Emergence of Streptococcus pneumoniae serotypes 19A, 6C, and 22F and serogroup 15 in Cleveland, Ohio, in relation to introduction of the protein-conjugated pneumococcal vaccine. Clin Infect Dis 2008;47(December (11)):1388–95. [22] Pilishvili T, Lexau C, Farley MM, Hadler J, Harrison LH, Bennett NM, et al. Sustained reductions in invasive pneumococcal disease in the era of conjugate vaccine. J Infect Dis 2010;201(January (1)):32–41. 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Vaccine journal homepage: www.elsevier.com/locate/vaccine
Early Streptococcus pneumoniae serotype changes in Utah adults after the introduction of PCV13 in children Brian A. Kendall a,∗,1 , Kristin K. Dascomb a,b,1 , Rajesh R. Mehta b , Chris Stockmann d , Edward O. Mason c , Krow Ampofo d , Andrew T. Pavia d , Carrie L. Byington d a
Departments of Medicine and Pathology, University of Utah, Salt Lake City, UT, USA Department of Infectious Diseases, Intermountain Healthcare, Murray, UT, USA c Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA d Department of pediatrics, University of Utah, Salt Lake City, UT, USA b
a r t i c l e
i n f o
Article history: Received 2 June 2015 Received in revised form 14 November 2015 Accepted 2 December 2015 Available online xxx Keywords: Streptococcus pneumoniae Invasive pneumococcal disease Pneumococcal vaccines Epidemiology
a b s t r a c t Introduction: Pneumococcal conjugate vaccines (PCV) have indirect effects due to decreased Streptococcus pneumoniae colonization in vaccine recipients. We sought to determine whether the introduction of PCV13 in children led to changes in the epidemiology and clinical manifestations of invasive pneumococcal disease (IPD) in adults. Methods: We described demographics, comorbidities, clinical manifestations, and serotypes of IPD in Utah adults before (November 2009−February 2010) and after (March 2010−March 2012) the introduction of PCV13 in children. We also compare serotypes causing IPD in Utah adults and children. Results: After the introduction of PCV13 in the childhood vaccine program, the proportion of IPD due to PCV13 exclusive serotypes decreased significantly in Utah adults (64−40%, p = 0.009), primarily due to a decline in serotype 7F (36−15%, p = 0.008). There were non-significant increases in IPD due to Pneumococcal polysaccharide 23 (PPV23) unique serotypes and non-vaccine serotypes, most notably serotype 22F. Changes in the proportions of vaccine and non-vaccine serotypes were similar in adults and children. Meningitis was more commonly due to non-vaccine serotypes relative to non-meningitis cases (47% vs. 18%, p = 0.007). When stratified by sex, decreases in PCV13 serotype IPD were only noted in men (76−33%, p = 0.001). Conclusions: Serotype epidemiology of IPD in adults closely follows that of children in the PCV13 era. Continued surveillance is needed to confirm whether replacement serotypes will lead to increases in pneumococcal meningitis and whether there are sex differences in the indirect effects of PCV vaccination in children. © 2015 Published by Elsevier Ltd.
1. Introduction The use of conjugate pneumococcal vaccines has resulted in selection pressure leading to rapid changes in the serotypes responsible for invasive pneumococcal disease (IPD) [1,2]. Conjugate vaccines not only impact the vaccine recipient, but also are thought to decrease pharyngeal carriage of Streptococcus pneumoniae via induction of mucosal antibodies [3] and possibly lead to indirect protection of vaccine non-recipients. The population effects of pneumococcal conjugate vaccines are complex and may lead to
∗ Corresponding author at: Departments of Medicine and Pathology, University of Utah, Salt Lake City, Utah, 30N 1900 E, Room 4B120, Salt Lake City, UT 84132, USA. E-mail address: [email protected] (B.A. Kendall). 1 The first two authors contributed equally to the preparation of this manuscript.
changes in both the epidemiology and the clinical manifestations of IPD. For instance, after the introduction of 7-valent pneumococcal conjugate vaccine (PCV7), changes in IPD complications such as empyema emerged rapidly in Utah children [4] prior to increasing nationally [5,6]. Empyema was most often due to serotypes not covered by PCV7 but included in the newer 13-valent pneumococcal conjugate vaccine (PCV13), including serotypes 1, 3, 7F, and 19A. We sought to determine if the institution of PCV13 in Utah children indirectly led to early changes in the serotypes responsible and the clinical syndromes seen in IPD in Utah adults.
2. Methods This study was approved by the institutional review boards of Intermountain Healthcare (Intermountain) and the University of
http://dx.doi.org/10.1016/j.vaccine.2015.12.010 0264-410X/© 2015 Published by Elsevier Ltd.
Please cite this article in press as: Kendall BA, et al. Early Streptococcus pneumoniae serotype changes in Utah adults after the introduction of PCV13 in children. Vaccine (2015), http://dx.doi.org/10.1016/j.vaccine.2015.12.010
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Table 1 Demographics, clinical characteristics, and outcome for adults PRE- and POST- approval of 13-valent pneumococcal conjugate vaccine.
Age by percentage <40 40-64 >65 Sex- percent male Race Caucasian Non-Caucasian Unknown PPV23 vaccination documented in EMR Comorbidities Alcohol abuse Diabetes HIV Neurologic disease Cardiovascular disease Pulmonary disease Renal disease Hepatic disease Hematologic malignancy Bone marrow transplant Solid organ malignancy Solid organ transplant Splenectomy Other immunocompromising therapy Clinical syndromes Bacteremia Occult bacteremia Bacteremic pneumonia Pleural effusion Meningitis Sinusitis Otitis media Mastoiditis Outcomes ICU admission Ventilator days (SD) Ever required vasopressors Death associated with hospitalization
PRE-PCV13 November 1, 2009−February 28, 2010 N = 36
POST-PCV13 March 1, 2010–March 31, 2012 N = 152
p-value
16.7 55.6 27.8 58.3
15.8 46.1 38.2 51.3
0.88 0.31 0.25 0.65
77.8 16.65.6 27.8
84.2 11.93.9 30.3
0.37 0.440.66 0.78
0 25.0 0 13.9 27.8 30.6 19.4 5.6 11.1 0 11.1 2.8 2.8 13.9
6.6 25.0 1.3 9.2 31.6 30.3 8.6 6.6 8.6 2.0 9.2 2.6 0.7 9.9
0.21 0.98 0.65 0.41 0.67 1.0 0.07 1.0 0.75 1.0 0.75 1.0 0.35 0.55
97.2 11.1 77.8 17.1 8.3 2.8 2.8 2.8
99.3 9.9 77.0 18.2 9.2 5.3 4.6 2.6
0.35 0.76 1.0 1.0 1.0 1.0 1.0 1.0
33.3 0.7(2.0) 11.1 5.6
32.2 1.7(3.9) 15.1 9.2
1.0 0.14 0.79 0.74
Utah. We systematically collected pneumococcal isolates from sterile site cultures obtained from adults 18 years and older cared for within the Intermountain Healthcare system from November 2009 through March 2012. All isolates were identified at the Intermountain central laboratory, and stored at the LDS Hospital clinical epidemiology laboratory. The central laboratory performs microbial identification for 18 of 20 Intermountain adult inpatient facilities, as well as several outpatient clinics. Intermountain Healthcare has an overall market share of 56% of the adult population in the state of Utah (approximately 2,040,000 adults in 2014). Streptococcus pneumoniae was identified by Gram stain, colony morphology, and optochin sensitivity. Identification was confirmed by the BD Phoenix Automated Microbiology System (BD Diagnostics, Franklin Lakes, NJ, USA). We performed serotyping on all isolates at the Baylor College of Medicine using the capsular swelling method [7]. IPD was defined as isolation of S. pneumoniae from blood, cerebrospinal fluid, ascites, pleural fluid, pericardial fluid, joint fluid, or internal body site. We obtained demographic, clinical, and microbiologic data from the Intermountain Enterprise Data Warehouse (EDW), an electronic storage site for data from patients receiving care at all Intermountain facilities. Two infectious diseases physician researchers (BK, KD) independently abstracted comorbidity data from available electronic physician notes. We considered comorbidities to be chronic diseases requiring ongoing medical care at the time of IPD. In cases where the two reviewers disagreed, classification of chronic diseases was adjudicated by group consensus.
Data regarding pneumococcal polysaccharide vaccination (PPV23) were abstracted from inpatient physician notes and electronic pharmacy records. Outpatient vaccine records were not available. We compared the frequency of clinical isolates included in PCV7, PCV13, PPV23, and non-vaccine serotypes identified before and again after the introduction of PCV13. We defined the ‘PRE’ period as November 1, 2009 through February 28, 2010 and the ‘POST’ period as March 1, 2010 through March 31, 2012. Isolates prior to November, 2009 were not archived, limiting the PRE period duration. PCV13 was licensed for use on February 24, 2010 and was rapidly introduced into the childhood vaccine schedule [8]. We performed additional univariate analyses stratifying by age and gender. We compared adult serotypes with IPD isolates collected from children under 18 treated during the same time periods at Primary Children’s Hospital. A detailed description of the pediatric cohort has been published previously [9]. Using SPSS for windows (IBM, Armonk, NY, USA), we examined associations between clinical and demographic characteristics of patients with individual serotypes and serotypes grouped by inclusion or exclusion from available vaccines. We used the Chi-square test or Fisher exact test for categorical variables and Student’s t-test or Mann-Whitney U-test for continuous variables. 3. Results We identified 200 isolates from 196 adults with cultureconfirmed IPD based on search of the EDW (Table 1). Six isolates
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did not exhibit capsular swelling when exposed to typed anti-sera and therefore serotype would not be determined. In addition, two isolates were from outpatients with no electronic medical records available for review, leaving 188 samples for analysis. There were no significant differences in demographic characteristics or comorbidities between the PRE- and POST-PCV13 groups (Table 1). Comorbidities were similar to those described in other cohorts [10].
Table 2 Changes in the frequency of Adult IPD Streptococcus pneumoniae serotypes before and after introduction of conjugated pneumococcal vaccine in Children in Utah, stratified by gender.
Gender Male PCV7 serotypes PCV13 serotypesa PPV23 serotypesb Nonvax serotypes Gender Female PCV& serotypes PCV13 serotypesa PPV23 serotypesb Nonvax serotypes
3.1. Serotype distribution of IPD isolates There were six isolates of PCV7 serotypes among Utah adults accounting for 3% isolates identified during the study period, 0 in the PRE period and six of 152 (4%) in the POST period. Serotypes exclusive to PCV13 declined, from 23/36 (64%) in the PRE period to 60/152 (40%) in the POST period (p = 0.009). (Figs. 1 and 2) This reduction is primarily due to a decrease in PCV13 serotype 7F, which accounted for 13/36 (36%) of isolates in the PRE period and declined to 23/152 (15%) of all isolates in the POST period (p = 0.008) A non-significant decrease was also seen in PCV13 type 3 but not in type 19A (Fig. 1). Serotypes in PPV23 but not in PCV13 increased from 9/36 (25%) in the PRE period to 55/152 (36%) in the POST period (p = 0.25). (Fig. 2a) PPV23 types 8 and 22F both increased slightly (1/36 [3%] to 14/152 [9%] (p = 0.25), and 2/36 [6%] to 17/152 [11%] (p = 0.39), respectively)(Fig. 1). Serotypes not present in any vaccine increased from 3/36 (8%) to 32/152 (21%) (p = 0.10). No individual serotype dominated in the POST period.
3.2. Comparison of adult and child serotype distributions There were 87 isolates collected from children (median age 2.9 {range: 0−15.8 years; 62% male): 12 in the PRE period and 75 from the POST period. The same trends were identified with nonsignificant decreases in the six additional serotypes contained in PCV13 (6/12 [50%] to 32/75 [43%] p = 0.79. PPV23 unique types and non-vaccine types increased (1/12 [1%] to 17/75 [23%] p = 0.46) and 1/12 [1%] to 23/75 [31%] p = 0.29, respectively). Changes in adult serotypes mirrored those in children (Fig. 2a for adults and Fig. 2b for children).
3.3. Serotypes and clinical presentation We observed no significant changes in clinical syndromes after the introduction of PCV13 (Table 1). Bacteremic pneumonia was the most common syndrome in both eras. There was no increase in the proportion of patients presenting with pleural disease. Across both eras, nearly half of the meningitis isolates were non-PCV13 types (8 of 17 [47%]). Non-PCV13 serotypes made up a significantly larger proportion of isolates from meningitis cases relative to nonmeningitis cases (8/17 [47%] vs. 30/171 [18%], [p = 0.007].
3.4. Serotype changes by sex When we stratified the data by sex, we found significant differences in the vaccine serotypes accounting for IPD in men and women (Table 2), though there was no difference in PPV23 vaccination rates between men and women (p = 0.78). Men had more disease due to the six additional PCV13 serotypes in the PRE-PCV13 era (PCV13 16/21 [76%] vs. 7/15 [47%] in women). In the POST PCV13 period, men had a significant decline in PCV13 serotypes isolated (decline to 26/78 [33%] [p = 0.001]) with no change demonstrated in women (7/15 [47%] in the PRE to 34/74 [46%] in the POST, p = 0.73).
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a b
PRE-PCV13 N = 36
POST-PCV13 N = 152
0% (n = 0) 76.2% (n = 16) 19.0% (n = 4) 4.8% (n = 1)
5.1% (n = 4) 33.3% (n = 26) 34.6% (n = 27) 26.9% (n = 21)
p = 0.42 p = 0.001 p = 0.23 p = 0.03
0 (n = 0) 46.7% (n = 7) 26.7% (n = 4) 26.7% (n = 4)
2.7% (n = 2) 45.9% (n = 34) 24.3% (n = 18) 27.0% (n = 20)
p = 0.68 p = 0.73 p = 0.68 p = 0.83
Six additional serotypes not present in PCV7. Serotypes unique to PPV23.
4. Discussion Our data demonstrate that the introduction of pneumococcal conjugate vaccines in the childhood immunization schedule has been associated with significant changes in the serotype distribution in Utah adults. PCV7 serotypes were rare and PCV13 unique serotypes significantly declined in both adults and children very soon after childhood vaccine introduction. Non-PCV-13 serotypes observed in adults mirrored those seen in the pediatric population and included serotypes found in the PPV23 (8 and 22F) and those that are not found in any licensed vaccine (16, and 35). We observed that meningitis cases were more often due to non-vaccine serotypes relative to non-meningitis cases. We identified a sexspecific effect on the distribution of serotypes causing IPD Introduction of PCV-7 into the pediatric vaccine schedule in 2000 lead to rapid and substantial declines in vaccine-type IPD[11] in all age groups, with the most dramatic decreases in young children targeted for immunization. PCV coverage in Utah has been excellent with greater than 80% of children 19−35 months of age receiving four PCV shots by by the end of 2011, providing strong potential for indirect immunity [12]. We previously reported a decrease in the frequency of vaccine-type IPD among Utah adults [13]. The continued absence of PCV7 serotypes and the decline in PCV13 serotypes in adults immediately after the introduction of PCV13 in children argues further that conjugate pneumococcal vaccines in children have a significant impact on the epidemiology of IPD in adults. Conjugate vaccines lead to decreased colonization in children due to the near elimination of vaccine-type pneumococci, likely leading to indirect protection of adults [14]. Our data suggest that indirect protection may emerge rapidly in adults after new conjugated vaccines are introduced in the childhood population. Prior to the introduction of PCV-13, serotype 7F was the most common cause of IPD among Utah adults and children [9,13,15]. This study demonstrated that following introduction of PCV13 serotype 7F declined rapidly and significantly in adults. The decline of type 7F in children was also significant when a longer-PRE period, unavailable for adult analysis, was evaluated (unpublished data). PCV13 serotype 3 declined, but not significantly, and 19A did not decline. One possible explanation is decreased type-specific vaccine immunogenicity [16,17] There is evidence that PCV13 does not lead to a robust immune response against serotype 3; in one study, only 64% of children mounted an adequate antibody response compared with 90−98% with the other new serotypes [18]. The reason that type 19A did not decline is unclear though another group reported persistent carriage rates of 19A in the POST PCV13 era [19]. The relatively high frequency of types 8 and 22F, serotypes of known pathogenicity [20], corresponds with increasing prevalence noted in other studies [21,22]. Both serotypes are components of
Please cite this article in press as: Kendall BA, et al. Early Streptococcus pneumoniae serotype changes in Utah adults after the introduction of PCV13 in children. Vaccine (2015), http://dx.doi.org/10.1016/j.vaccine.2015.12.010
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Fig. 1. Changes in IPD serogroup/type frequency by proportion of the total isolates for the periods PRE and POST introduction of 13 valent conjugated pneumococcal vaccine in children, February 2010 (n = 188).
Fig. 2. Changes in the proportion of vaccine type IPD in (a) adults and (b) children PRE and POST introduction of PCV13. PPV23 serotypes are those unique to this vaccine. PCV13 serotypes are the six additional types not present in PCV7.
PPV23 but inclusion of these types in future conjugate vaccines may also be beneficial. The large proportion of non-vaccine serotypes among meningitis cases may be reason for concern. Non-vaccine serotypes 35B, 35F, 15C, and 6C were present in our meningitis cohort and have been associated with meningitis in Utah children, as well as adults and children from national surveillance data. [23,24]. Continued national and regional surveillance will be critical to determining whether serotype replacement will result in increasing meningitis frequency as was determined with empyema [5,6,25]. The differential representation of serotypes by sex has not been previously reported. This result may be explained by differences in
the immunogenicity of polysaccharide vaccines. Many viruses and bacteria have been shown to induce different antibody responses in men and women [26,27] and anthrax vaccines cause more localized inflammation in women than in men [26]. Recently, Wiemken et al. [28] found that PPV23 protected women older than 65 from hospitalization due to pneumococcal pneumonia but did not protect men. In our cohort, men had more PRE-PCV13 disease due to vaccine types included in both PCV13 and PPV23 (of which there is considerable overlap), a finding that could be explained by less effective PPV23 vaccine response. The increase (though nonsignificant) in disease due to PPV23 unique serotypes in men and stability of such disease in women also supports this hypothesis.
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While the numbers in our study are small, if this finding is confirmed in larger cohorts, men may realize more indirect benefit of pediatric conjugate vaccines. Our study has several limitations. Our cohort is not truly population-based, however Intermountain Healthcare provides 56% of the medical care for adults and 85% of care for children in Utah and we believe that our results are likely representative of IPD in our region. We only collected isolates from sterile sources; therefore, our data are only representative of serotypes involved in invasive disease and may not be representative of serotypes causing localized disease (e.g. sinusitis, otitis media, pneumonia without bacteremia). In spite of these limitations, our data provide evidence that conjugate vaccines in children produce indirect protective effects in adult IPD remarkably soon after their introduction into the community. Serotype replacement also appears to occur quickly and may have clinically significant consequences [2,29]. A difference in vaccine response between genders deserves close scrutiny as a possible factor in vaccine effectiveness. Funding This work was supported by Intermountain Healthcare and the University of Utah. Acknowledgments The authors would like to thank George Hinde and Esar Chickrie for laboratory assistance. Conflict of interest statement BAK is supported by an investigator-initiated grant from Merck and Co., Inc. to study methods for the diagnosis of communityacquired pneumonia due to S. pneumoniae. KKD is supported by an investigator-initiated grant from Pfizer, Inc. to study pneumococcal serotype distribution in Utah adults with pneumonia. CS is supported by the American Foundation for Pharmaceutical Education’s Clinical Pharmaceutical Sciences Fellowship. CLB has intellectual property in and receives royalties from BioFire Diagnostics. CLB is supported by NIH/NCATS 1UL1TR001067 and by the HA and Edna Benning Presidential Endowment. References [1] Moore MR, Link-Gelles R, Schaffner W, Lynfield R, Lexau C, Bennett NM, et al. Effect of use of 13-valent pneumococcal conjugate vaccine in children on invasive pneumococcal disease in children and adults in the USA: analysis of multisite, population-based surveillance. Lancet Infect Dis 2015;15(March (3)):301–9. [2] Stockmann C, Byington CL. PCV13 in the USA: early successes and potential challenges. Lancet Infect Dis 2015;15(March (3)):254–6. [3] Ghaffar F, Barton T, Lozano J, Muniz LS, Hicks P, Gan V, et al. Effect of the 7-valent pneumococcal conjugate vaccine on nasopharyngeal colonization by Streptococcus pneumoniae in the first 2 years of life. Clin Infect Dis 2004;39(October (7)):930–8. [4] Ampofo K, Pavia AT, Stockmann CR, Blaschke AJ, Weng HY, Korgenski KE, et al. Evolution of the epidemiology of pneumococcal disease among Utah children through the vaccine era. Pediatr Infect Dis J 2011;30(December (12)):1100–3. [5] Li ST, Tancredi DJ. Empyema hospitalizations increased in US children despite pneumococcal conjugate vaccine. Pediatrics 2010;125(January (1)):26–33. [6] Grijalva CG, Nuorti JP, Zhu Y, Griffin MR. Increasing incidence of empyema complicating childhood community-acquired pneumonia in the United States. Clin Infect Dis 2010;50(March (6)):805–13.
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Please cite this article in press as: Kendall BA, et al. Early Streptococcus pneumoniae serotype changes in Utah adults after the introduction of PCV13 in children. Vaccine (2015), http://dx.doi.org/10.1016/j.vaccine.2015.12.010